inVentiv Health Research Articles

382TiP - CONTESSA TRIO: A multinational, multicenter, phase II study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with her2- metastatic breast cancer (MBC)

382TiP - CONTESSA TRIO: A multinational, multicenter, phase II study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with her2- metastatic breast cancer (MBC)

First in Human Single-Ascending Dose Study: Safety, Biomarker, Pharmacokinetics and Exposure-Response Relationships of ALXN1210, a Humanized Monoclonal Antibody to C5, with Marked Half-Life Extension and Potential for Significantly Longer Dosing Intervals

▪Introduction: ALXN1210 is a humanized monoclonal antibody (mAb), with a sequence closely related to eculizumab (Soliris®). ALXN1210 binds specifically to human complement protein C5 and was engineered to eliminate the formation of C5a and the terminal complement complex with extended duration of complete complement inhibition. The mechanism of action of ALXN1210 provides strong clinical rationale for potential therapeutic use in patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, and other complement-mediated diseases. Clinical experience with eculizumab supports the reduction of free C5 to undetectable levels for complete inhibition of hemolysis.Methods: In this Phase 1, randomized, blinded, placebo-controlled, single-ascending dose study, healthy subjects received a single intravenous (IV) dose of 200 mg (cohort 1) or 400 mg (cohort 2) ALXN1210 or placebo (PBO), and were then followed for 150 days. Subjects were vaccinated with a tetravalent conjugate N. meningitidis vaccine and received prophylactic penicillin V. The primary objective was to evaluate the safety and tolerability of a single dose of ALXN1210. Secondary objectives were to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ALXN1210. PD effects of ALXN1210 were assessed as the change in serum free C5 and ex vivo (cell-based) hemolytic activity.Results: Fourteen subjects enrolled in the study: 4 received 200 mg ALXN1210, 6 received 400 mg ALXN1210, and 4 received PBO. Serum ALXN1210 concentrations were measureable for the entire 150-day follow-up period. Mean Cmax and AUC∞ increased in a dose-proportional manner, with a mean terminal half-life of approximately 32 days and low (<20%) intersubject variability in PK parameters.Levels of free C5 were reduced by >99% from baseline in all subjects who received ALXN1210. Additionally, all subjects who received a single dose of 400 mg ALXN1210 reached or exceeded the ALXN1210 threshold level of 100 µg/ml and had >99% elimination of free C5. For subjects with ALXN1210 levels >100 µg/ml, average elimination of C5 was >99%. No reductions in free C5 concentrations were observed in subjects who received PBO. Mean chicken red blood cell (cRBC) hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210. The duration of suppression of mean cRBC hemolysis was dose dependent. No anti-drug antibody (ADA) response was observed during the 150-day follow-up period.Seven subjects (70%) receiving ALXN1210 reported 21 treatment-emergent adverse events (TEAEs); 3 in cohort 1 (200 mg) reported 6 TEAEs, and 4 in cohort 2 (400 mg) reported 15 TEAEs. The most frequently reported event was headache in subjects receiving ALXN1210 (3 subjects [50%], 3 events) or PBO (3 subjects [75%]; 7 events). Most (17/21; 81%) TEAEs were reported as mild, and all resolved during the trial. No drug-related serious AEs or treatment discontinuations due to TEAEs were reported.Conclusions:•Single IV doses of 200 mg or 400 mg ALXN1210 were well tolerated in healthy subjects.•Serum ALXN1210 concentration data exhibited a terminal half-life of 32 days-longer than eculizumab (9 days).•Mean ALXN1210 Cmax and AUC∞ increased in a dose-proportional manner.•100% of subjects who received ALXN1210 had samples with >99% elimination of free C5.•In subjects who received a single IV 400-mg dose of ALXN1210: •100% reached or exceeded the ALXN1210 threshold level of 100 µg/mL;•100% obtained >99% elimination of free C5;•Mean elimination of free C5 was >99%.•For ALXN1210 levels >100 µg/ml, average elimination of free C5 was >99%.•Mean cRBC hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210, and duration of suppression of mean cRBC hemolysis was dose dependent.•No ADA response was observed after a single dose of ALXN1210 during the 150-day follow-up period.•Data modeling supports that >99% elimination of free C5 will be achieved with doses of ALXN1210 administered at 4-week or longer dosing intervals.A multiple ascending dose study is ongoing, and 2 studies examining the safety, tolerability, efficacy, PK, and PD of ALXN1210 administered at ≥4-week dosing intervals will be initiated in PNH patients before the end of 2015. DisclosuresSahelijo:Alexion Pharmaceuticals: Employment, Equity Ownership. Mujeebuddin:Alexion Pharmaceuticals: Employment, Equity Ownership. Mitchell:Alexion Pharmaceuticals: Consultancy. Larouche:Inventiv Health: Employment, Other: Inventiv Health Conducted the Study; Alexion Pharmaceuticals: Other: Principal Investigator Of Trial Related to Abstract, Research Funding. Yu:Alexion Pharmaceuticals: Employment, Equity Ownership. Zhang:Alexion Pharmaceuticals: Employment, Equity Ownership. Patel:Alexion Pharmaceuticals: Employment, Equity Ownership. Lasaro:Alexion Pharmaceuticals: Employment. Bouchard:Alexion Pharmaceuticals: Employment. Andrien:Alexion Pharmaceuticals: Employment. Wang:Alexion Pharmaceuticals: Employment. Tamburini:Alexion Pharmaceuticals: Employment, Equity Ownership. Macdonald:Alexion Pharmaceuticals: Employment, Equity Ownership. Sheridan:Alexion Pharmaceuticals: Employment, Equity Ownership. Soni:Alexion Pharmaceuticals: Employment, Equity Ownership.

The importance of choosing the appropriate matrix to validate a bioanalytical method according to the study needs.

Sylvain Lachance is a Bioanalytical Scientific Expert in the Bioanalytical Division of inVentiv Health Clinical Quebec City's (Canada) site, a CRO offering clinical, commercial and consulting services to the healthcare industry. He is responsible for following up on the conduct of bioanalytical method development activities by enhancing the scientific and technical knowledge of the researchers, bioanalytical project coordinators and of the laboratory technicians. He assists bioanalytical project coordinators in investigations during bioanalyses and method validations. He has been working in the Bioanalytical Division of inVentiv Health Clinical for over 16 years, working as a Research Scientist, Chromatographic Specialist and Scientific Expert. He has worked on multiple method developments in HPLC and LC-MS/MS, specifically on troubleshooting. He has been involved in more than 70 posters and publications in the bioanalytical field for different scientific meetings. Ann Lévesque obtained her PhD in Biochemistry at the Université Laval in Québec City in 1994 studying the biological actions of peptide analogs of the gastrin releasing peptide in the growth inhibition of cancer cells. Prior to joining inVentiv Health Clinical, she held management positions at other Contract Research Organizations. Her publications include over 100 posters, 17 scientific articles and book chapters in the clinical biochemistry and bioanalytical fields. Within inVentiv Health, Dr. Lévesque is responsible for managing the R&D and sample analysis teams performing bioanalytical analysis of small molecules and peptides. She is also acting as the Biomedical Laboratory Director accountable for the oversight of all activities related to the safety testing of samples from subjects enrolled in early stage clinical trials. Since joining the Bioanalytical Division, Dr. Lévesque has been instrumental in the great success of the laboratory by developing a culture of quality, innovation and value. Validation guidelines from different agencies mainly recommend that matrix effect should be studied with hemolyzed and hyperlipidemic samples, while the European agency requires also to investigate matrix effect on special population. When studies are done in countries with different dietary habits, or when a medication is administered to decrease the concentration of the endogenous compounds, should the matrix effect in these conditions be evaluated? Herein, three case studies are described to show the importance of choosing the appropriate matrix for the bioanalytical method validations and for their use to analyze the study samples according to the conditions required by the clinical trials. The case studies presented are related to the use of the testosterone, Omega-3 and cortisol methods.

Evaluation of Antitumor Activity Using Change in Tumor Size of the Survivin Antisense Oligonucleotide LY2181308 in Combination with Docetaxel for Second-Line Treatment of Patients with Non–Small-Cell Lung Cancer: A Randomized Open-Label Phase II Study

Chemoresistance is mediated, in part, by the inhibition of apoptosis in tumor cells. Survivin is an antiapoptotic protein that blocks chemotherapy-induced apoptosis. To investigate whether blocking survivin expression enhances docetaxel-induced apoptosis in patients with non-small-cell lung cancer (NSCLC), we compared the antitumor activity of the survivin inhibitor LY2181308 plus docetaxel with docetaxel alone. We used change in tumor size (CTS) as a primary endpoint to assess its use in early decision-making for this and future studies of novel agents in NSCLC. Patients (N = 162) eligible for second-line NSCLC treatment (stage IIIB/IV) with an Eastern Cooperative Oncology Group performance status of 0 to 1 were randomized 2:1 to receive LY2181308 (750 mg intravenously, weekly) and docetaxel (75 mg/m intravenously, day 1) or docetaxel alone every 21 days. CTS from baseline to the end of cycle 2 was compared between the two treatment arms. The mean (SD) tumor size ratio for LY2181308/docetaxel and docetaxel was 1.05 (0.21) and 1.00 (0.15) (p = 0.200), respectively, suggesting no significant improvement in antitumor activity between the arms. Because there was also no significant difference between the two arms for progression-free survival (PFS) (2.83 months with LY2181308/docetaxel and 3.35 months with docetaxel [p = 0.191]), both arms were combined. Using the combined arms, CTS correlated with PFS (PFS = 4.63 months in patients with decreased CTS compared with 2.66 months in patients with increased CTS), supporting its use in early decision-making in phase II studies.

SAT0395 Scalp Psoriasis as A Surrogate Marker for Psoriatic Arthritis Severity and Treatment Response

BackgroundPatients with psoriasis (PsO) are at an increased risk of developing psoriatic arthritis (PsA).1 It has been observed that scalp PsO is indicative of more severe PsO, and increased PsO...

FRI0260 High Rates of Remission Induction Achieved with Combination Etanercept Plus Methotrexate in Early Rheumatoid Arthritis up to One Year after Symptom Onset

BackgroundThe outcome of etanercept plus methotrexate (ETN+MTX) combination therapy for early rheumatoid arthritis (RA) is often best when patients (pts) are treated early,1 but identification of those who would most...

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